17-7676225-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1 PM2 BP4_Moderate BP6_Very_Strong

The NM_000546.6(TP53):c.144C>A(p.Asp48Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D48G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:2
• Conservation: PhyloP100: -3.11

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08270705).
• BP6: Variant 17-7676225-G-T is Benign according to our data. Variant chr17-7676225-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 141056.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.144C>A	p.Asp48Glu	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.144C>A	p.Asp48Glu	missense_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 58 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2 Benign:1

Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Sep 04, 2020	Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, TP53 c.144C>A (p.Asp48Glu) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, PM2_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 23, 2023	This missense variant replaces aspartic acid with glutamic acid at codon 48 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant did not impact function in yeast transactivation assays (PMID: 12826609) and human cell growth suppression assays (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 48 of the TP53 protein (p.Asp48Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 141056). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2023	This missense variant replaces aspartic acid with glutamic acid at codon 48 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that this variant did not impact function in yeast transactivation assays (PMID: 12826609) and human cell growth suppression assays (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	0.0096	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	0.0010
Dann	Benign	0.22
DEOGEN2	Benign	0.0030	T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.54	T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.25	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T;T;.;T;.;.;T;T;.;.;T;.;.;T;.;T
Sift4G	Benign	0.84	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.0	B;.;.;B;.;B;B;B;.;.;B;.;.;B;.;.
Vest4		0.057
MutPred		0.16		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;.;Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.71
MPC		0.60
ClinPred		0.030	T
GERP RS		-5.0
Varity_R		0.31
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781460; hg19: chr17-7579543;